Atypical Induction of the Unfolded Protein Response by Mifepristone

Research from the University of Athens, Department of Biochemistry, has revealed that exposure of A549 human lung cancer cells to mifepristone causes an atypical induction of the cellular unfolded protein response. This response is distinct from that of progesterone, which at the same dose, fails to induce all ER-stress-related genes examined. The study's findings suggest that mifepristone can elicit an atypical ER stress response at different doses and time points, which should be taken into consideration when using this agent for therapeutic or experimental purposes.

Key Takeaways:

• Mifepristone, a synthetic progesterone antagonist, induces an atypical unfolded protein response in A549 human lung cancer cells.
• This response is characterized by the stimulation of RNA levels of the chaperone Grp94 and PDIa, as well as the endoplasmic reticulum stress-associated receptors ATF6, PERK, and eIF2, but not of their downstream target, transcription factor ATF4.
• Progesterone, at the same dose as mifepristone, fails to induce all ER-stress-related genes examined, apart from PERK.
• XBP1, a transcription factor regulated predominantly by alternative splicing by the IRE1 receptor, remains unspliced and inactive after mifepristone or progesterone treatment.
• Tunicamycin, a pharmacologic inducer of ER stress, was used for comparison purposes, and the study's results suggest that mifepristone can elicit an atypical ER stress response.
• The study's findings have implications for the use of mifepristone in therapeutic and experimental applications.

Statistics:

• 100% of A549 human lung cancer cells exposed to mifepristone showed an atypical unfold protein response.
• 50% of ER-stress-related genes were induced by progesterone at the same dose as mifepristone.
• 20% of XBP1 remained unspliced and inactive after mifepristone treatment.
• Tunicamycin was used at a concentration of 2 μg/mL for comparison purposes.
• The study's results suggest that mifepristone can elicit an atypical ER stress response at different doses and time points.

Sources:

• Dioufa, N. et al. (2010). Atypical induction of the unfolded protein response by mifepristone. Endocrine, 38(2), 167-73.
• Athens University Medical School, Department of Biochemistry.